Department of Physiology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2113813119. doi: 10.1073/pnas.2113813119. Epub 2022 Mar 8.
SignificanceThe GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 () gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of ALS patients remain elusive. Here, we show that the proline-arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the Nav1.2/β4 sodium channel complex, which is highly expressed in the motor cortex. These findings provide the basis for understanding how the mutation causes motor neuron hyperactivation that can lead to the motor neuron death in ALS.
染色体 9 开放阅读框 72 （）基因中的 GGGGCC 六核苷酸重复扩展是肌萎缩侧索硬化症（ALS）最常见的遗传原因。尽管对重复产生的多二肽的毒性作用进行了大量研究，但导致 ALS 患者早期特征性运动皮层过度兴奋的机制仍难以捉摸。在这里，我们表明脯氨酸-精氨酸多二肽通过增加在运动皮层中高度表达的 Nav1.2/β4 钠通道复合物传导的持续钠电流，使皮质运动神经元过度兴奋。这些发现为理解突变如何导致运动神经元过度激活，从而导致 ALS 中的运动神经元死亡提供了基础。
